Inside the Vioxx Debacle

By Jon VanZile

April 2005

By Jon VanZile

Vioxx®: Tip of the Iceberg?

The situation might not be so bad if Vioxx® were an isolated case. But it is not. In recent years, other FDA scientists have come forward with their own stories. Unfortunately, the treatment they received was no better than the intimidation directed at Dr. Graham.

“I wasn’t surprised at the FDA’s reaction because the tradition at the FDA has been to react negatively to new information that illustrates how the FDA’s policies are inadequate or wrong,” Dr. Graham said. “When you illustrate that the FDA’s policies are harmful, the reaction is negative and immediate.”

In fact, Dr. Graham was the second FDA scientist to appear before the Senate Finance Committee in late 2004. The first was Dr. Andrew Mosholder, an FDA epidemiologist who testified last fall that FDA superiors had asked him to soften recommendations concerning antidepressants.

In 2004, Dr. Mosholder conducted a meta-analysis of 22 studies on the use of antidepressants in children. His research showed that children who took antidepressants, such as Prozac® and Zoloft®, were twice as likely to become suicidal as children who took a placebo.

Once again, however, senior FDA officials intervened before Dr. Mosholder could make his results public. Dr. Mosholder was told to alter his research findings in material that was submitted to Congress, and was threatened with disciplinary action by the FDA’s Office of Internal Affairs if he went to the media. On another occasion, he was barred from testifying at a public hearing on antidepressants and children.

And once again, there had been warning signs. According to the Senate investigation, the link between antidepressants and children had been studied since 1996, yet no drug label changes were made and no drugs were taken off the market.

“There is something terribly rotten at the FDA,” Rep. Peter Deutsch (D-FL) told the Los Angeles Times after Mosholder’s testimony. “No agency charged with protecting the public health should have behaved with such indifference.”3

The only thing unusual about these cases is that they became public, according to Dr. Graham. In fact, without urgent reform at the FDA, it seems almost inevitable that another Vioxx®-sized disaster will occur. Dr. Graham himself has identified several other drugs that demand immediate action:

Meridia®, used for weight loss, has been associated with high blood pressure and stroke.

Crestor®, used to lower cholesterol, has been associated with renal failure and other serious side effects.

Accutane®, used to treat acne, has been linked to birth defects, and Dr. Graham believes its sale should be restricted immediately.

Serevent®, used to treat asthma, can actually aggravate and cause death due to asthma.

Dr. Graham, along with other consumer groups such as Public Citizen, are calling on the FDA to scrutinize other COX-2 inhibitors, such as Bextra® and Celebrex®. In late January 2005, Public Citizen filed a petition with the FDA, demanding that it remove Bextra® and Celebrex® from the market.

“The Food & Drug Administration should immediately ban the sale of Celebrex® and Bextra®, which put millions of people, many of them elderly, at risk of heart attack,” said Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group. “These drugs are not only more expensive and more dangerous than older, safer pain relievers, they are no better at protecting the gastrointestinal tract.”

Even the FDA’s own scientists lack faith in the agency’s ability to protect the American people. December 2004 saw the release of a previously unpublished FDA internal management review, in which 846 FDA scientists were asked to complete an extensive survey. About half answered. The study found that:

Two thirds of FDA scientists lack confidence that the agency “adequately monitors the safety of prescription drugs once they are on the market.”

More than a third (36%) were not at all or only somewhat confident that “final decisions adequately assess the safety of a drug.”

Nearly 20% said they “have been pressured to approve or recommend approval [for a drug] despite reservations about the safety, efficacy, or quality of the drug.”

With findings like these, it is no wonder the FDA tried to prevent the survey from ever seeing the light of day. In fact, it might never have been made public if not for the efforts of two public interest groups, Public Employees for Environmental Responsibility (PEER) and the Union of Concerned Scientists (UCS).

“Many concerns had been raised about the manipulation of science within the [Bush] administration,” said Suzanne Shaw, UCS director of communications. “There had also been concerns raised at the FDA. In thinking about how to design a tool to get more data, we heard about the survey. But when we tried to see the actual results, we were told we couldn’t see the report.”

Eventually, it took a request under the Freedom of Information of Act to pry the report loose from the FDA.

WHAT ABOUT CELEBREX®?

In the latter half of September 2004, as the world focused on the dangers associated with Vioxx®, many people were quick to ask about other COX-2 inhibitors such as Celebrex®. Is Celebrex® safe, or are people putting their health at risk by taking it?

Media sources around the country initially reported that Celebrex® is safe. No study had shown increased risk of heart attack or stroke associated with its use. In fact, after the FDA added a mild warning to the Vioxx® label in 2000, sales of Celebrex® surged while those of Vioxx® remained flat or grew slowly. Pfizer, the maker of Celebrex®, rushed a statement to the media proclaiming that its COX-2 inhibitor is safe.

Not so fast.

In December 2004, researchers discontinued a study of Celebrex® after they found that the drug is, in fact, associated with heart attack and stroke.4 The study originally sought to determine whether Celebrex® could help prevent colon cancer. At the time, Pfizer said it was surprised by the study results.

In early February 2005, however, the New York Times reported on a five-year-old clinical trial that contradicted Pfizer’s contentions. The trial, begun in 1999, showed that the number of Celebrex® patients who suffered a heart attack was almost four times that of patients taking a placebo. Pfizer’s own scientists found the difference to be statistically significant.5

The study, however, was never published, and it was not submitted to the FDA until June 2001. It was not released to the public until early 2004, when researchers for the public interest group Public Citizen discovered it on a website where pharmaceutical companies had begun posting clinical trials.

Based on this new study, Public Citizen petitioned the FDA in January 2005 to take Celebrex® and Bextra® (another COX-2 inhibitor) off the market, saying both drugs are unacceptably dangerous and do not provide any additional benefits compared to similar medications.

Serving Drug Companies, Not the Public

Dr. Graham is certain that without urgent reform, Vioxx® is only the beginning of the disasters that will flow from FDA incompetence and arrogance. Congress must act, because the FDA’s problems are so fundamental that nothing except reform forced on the agency from the outside can work.

The basic problem, according to Dr. Graham, is that the FDA does not serve the American public, but instead serves the pharmaceutical industry.

Under FDA regulations, pharmaceutical companies submit new drugs to the FDA’s Office of New Drugs. These companies are always racing against time because their drugs are protected by a patent for only 17 years, which includes the time it takes to get the drug approved in the first place.

To speed drug approval, the FDA charges fees to pharmaceutical companies during the approval process. The fees help “expedite” the complicated but required evaluation of human and animal studies. This means that the FDA accepts money from the very industry it is supposed to regulate.

“You want to be evidence based, but the FDA would rather suspend its judgment so it can better serve its clients: industry,” said Dr. Graham.

This process results in a biased flow of information, dictated almost entirely by pharmaceutical companies. During the approval process and afterward, the drug makers are not required to release studies that reflect poorly on their drugs.

The real trouble begins, however, once a drug is approved. No matter how extensive the pre-approval process, there is no substitute for experience. In the case of Vioxx®, the drug was approved based on studies involving 5,000 subjects. That may seem like a lot, but it is a tiny fraction compared to the millions who eventually used Vioxx®. Sometimes researchers do not and cannot learn about a dangerous drug until they study the side effects across whole populations of people.

Given the way the FDA is structured, however, that almost never happens. Dr. Graham launched a study on Vioxx® after its approval, and that is the exception rather than the norm. In most cases, once drugs are approved, no further steps are taken to ensure their safety. In fact, the FDA culture actively discourages scientists from pursuing safety concerns in approved drugs, according to Dr. Graham. And that goes for the manufacturer as well.

“There’s no incentive for the company to do post-marketing studies,” said Dr. Graham. “They’ve already been given a free pass on safety. It’s all downside for the company, and the FDA has no incentive to do post-marketing studies because it only cares about getting new drugs on the market. The FDA’s main client is industry.”

As Dr. Graham’s story demonstrates, once questions are raised, the Office of New Drugs is willing to say or do virtually anything—including pressuring its senior scientists to alter their conclusions, and even trying to destroy their careers and reputations—to protect drug company interests.

As long as the FDA remains beholden to the pharmaceutical companies, financially and otherwise, it will be unable to protect the American public. Considering the FDA’s recent history, there is no reason to believe the agency can reform itself. The only real hope is that Congress will act to dismantle and rebuild the FDA from the ground up.

“Right now, it’s the FDA’s fault, but if it happens again, Congress will be partly responsible,” said Dr. Graham. “I’m an idealist. I hope people can rise above their political philosophy and unite to create a system of drug safety. If they don’t unite, another disaster will come, and it might be a family member of someone in Congress. Then they will become believers. The men and women in Congress need to understand that these are people’s lives.”

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